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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Induction of hepatic CYP2E1 by a subtoxic dose of Acetaminophen in rats: increase in Dichloromethane metabolism and carboxyhemoglobin elevation
Author:
Kim SN, Seo JY, Jung DW, Lee MY, Jung YS, Kim YC
Year:
2007
Bibliographic source:
Drug Metab Dispos 35 (10): 1754-1758

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
DCM metabolism studied together with COHb elevation
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
corn oil
Duration and frequency of treatment / exposure:
Single treatment (see below)
Doses / concentrations
Remarks:
Doses / Concentrations:
3 mmol/kg bw
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle

Results and discussion

Preliminary studies:
Serum AST, ALT, and SDH activities were determined in female rats treated with APAP at various doses (250–1000 mg/kg). At 18 h after the treatment serum enzyme activities were not elevated by an APAP dose of up to 500 mg/kg. Starting from the APAP dose of 750 mg/kg, the enzyme activities were increased, although the difference from control was not statistically significant until the dose reached 1000 mg/kg. In this study the maximal dose of APAP that did not influence the serum parameters in rats under normal feeding was determined to be 500 mg/kg. Therefore, all the subsequent experiments were conducted with this dose level.

Any other information on results incl. tables

In rats treated with a dose of DCM, blood COHb levels were elevated rapidly, reaching a peak of 11% at 3 h after the treatment. A dose of APAP 18 h before the DCM challenge enhanced the increase in COHb levels significantly. Elevation of COHb levels seemed to be more rapid, and the peak was higher in rats pretreated with APAP compared with that in rats treated with DCM only. The COHb levels of both groups returned to near-normal values

in 6 h. An increase in the capacity of the oxidative metabolic pathway for DCM was observed. This manifested as slight upregulation of CYP2E1 (and 3A4) at the protein and enzymatic level leading to an increase in the metabolic clearance of DCM associated with a slight, but significant, increase in the amount of COHb formed and its rate of increase.

Applicant's summary and conclusion

Executive summary:

It is now recognised that CYP2E1 is the main P450 isoform responsible for the oxidative metabolism of DCM, both in humans and rodents. This pathway leads, via an unstable formyl chloride intermediate, to the generation of carbon monoxide and carbon dioxide; indeed, the main overt effect observed in DCM-exposed humans is reduced oxygen carrying capacity due to the formation of carboxyhaemoglobin (COHb).

Limited evidence suggests that modulation of CYP2E1 expression may affect the metabolic disposition of DCM and consequent increases in blood COHb, at least with acute exposure. When female Sprague-Dawley rats (n=6 per group) were dosed with acetaminophen (500 mg/kg i.p.), an increase in the capacity of the oxidative metabolic pathway for DCM was observed. This manifested as slight upregulation of CYP2E1 (and 3A4) at the protein and enzymatic level leading to an increase in the metabolic clearance of DCM (3 mmol/kg i.p. administered 18 hours after acetaminophen) associated with a slight, but significant, increase in the amount of COHb formed and its rate of increase. It did not seem to involve GSTT1 since no change in hepatic glutathione levels or EPNP activity was observed.